The objective of this project is to understand the function of SAM domains. SAM domains are frequently occurring protein modules that bind to themselves, to other SAM domains and to other non-SAM domain containing proteins. They are important for building regulatory protein complexes in the cell. Our work in the prior grant period has demonstrated that SAM domains can form a diverse array of oligomers, ranging from polymeric structures to discrete, closed oligomers. We have obtained high-resolution structures of three different SAM polymers, but this only represents a fraction of the different protein interaction modes utilized by SAM domains. In the current application, we propose to: Determine the structures of three more polymers, a structure of a hetero-polymeric ioint made by two different SAM domains, and the structure of discrete oliqomer. These structures will reveal new modes of SAM interactions. Investigate the role of SAM polymerization in transcriptional repression. We have discovered that many repressors contain polymeric SAM domains. We hypothesize that the SAM polymers play a role in the spreading of transcriptional repression and proposed a model of silenced chromatin structure, organized around a SAM polymer. We plan to test these ideas in this proposal. Test a new anti-leukemia drug strategy. The TEL gene is frequently involved in chromosomal translocations, leading to oncogenic fusions of the TEL-SAM domain to a variety of other protein domains including protein tyrosine kinases. TEL-SAM polymerization leads to constitutive activation of these tyrosine kinases, which in turn leads to a variety of hematalogic malignancies. We have developed protein inhibitors of TEL-SAM polymerization and plan to test whether these inhibitors can block cell transformation by the TEL oncogenes.